Cyclin dependent kinases (Cdks) are essential enzymes for the control of cell cycle progression. Inhibitors of cyclin-dependent kinases are anticipated to possess therapeutic utility against a wide variety of proliferative diseases, especially cancer. As a result of this, the CDKs have been targeted for drug discovery and a number of small molecule inhibitors of CDKs have been identified and studied. Inhibitors of CDK/cyclin complexes represented by the following general Formula 1;
wherein Ar is defined in the detailed description;have been described in PCT Patent Application No. PCT/IB2006/052002, which is incorporated herein by reference. These compounds exhibit good selectivity and cytotoxicity against various proliferative cell lines. The novel compounds disclosed in the aforesaid patent application, have two chiral centers and hence, can exist as four enantiomers i.e. (+)-trans, (−)-trans, (+)-cis and (−)-cis. Chirality has acquired increasing importance for the pharmaceutical industry, as evidenced by the fact that more than 80% of the drugs developed hitherto have chiral properties. The various enantiomers may develop completely different effects in the body, so that only one of two or more enantiomeric forms administered may be effective. In the case of the compounds of Formula 1, it has been observed that only the (+)-trans enantiomers have activity while the (−)-trans enantiomers are inactive. An extensive study by the present inventors of the efficacy of the racemic compounds of Formula 1 and their separate enantiomers has resulted in the applicant's PCT Patent Application No. PCT/IB2006/052002. Administration of the active (+)-trans enantiomer of any of the compounds represented by Formula 1, substantially free of its other isomers, would essentially enable a reduction in the dose of drug. Due to the importance of the (+)-trans enantiomers of the compounds represented by Formula 1 as inhibitors of cyclin dependant kinases, there exists a need to develop an economical and efficient synthetic process for their production.
Applicant's PCT Patent Application No. PCT/IB2006/052002 describes a process for the preparation of the (+)-trans enantiomer of a pyrrolidine substituted with a flavone represented by the following Formula 1;
wherein Ar is defined in the detailed description.
The process as described in the PCT Patent Application No. PCT/IB2006/052002 involves resolution of an intermediate compound and subsequent conversion of the resolved intermediate compound to the compound represented by Formula 1. For instance, (+)-trans-2-(2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one was prepared by resolution of an intermediate, namely (±)-trans-[1-methyl-3-(2,4,6-trimethoxy-phenyl)-pyrrolidin-2-yl]-methanol, and subsequent conversion of the (−)-trans isomer of the intermediate to (+)-trans-2-(2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one. The preparation of the (−)-trans-isomer of the intermediate involves the steps of treating its racemate with a chiral auxiliary to obtain the corresponding (+)- and (−)-trans diastereomeric salts followed by separating the desired diastereomeric salt by crystallization and treating it with a base to yield the desired (−)-trans enantiomer. This resolution method involves significant processing and also the use of resolving agent renders the process costly. Partial recycling of the resolving agent is feasible but such recycling is costly as it requires additional processing and is also associated with waste generation. The undesired enantiomer cannot be recycled and is discarded. The maximum theoretical yield of the key intermediate obtained is just 50% on a laboratory scale synthesis due to loss of half of the racemate. This yield may be further reduced due to the need for high chiral purity (>95% enantiomeric excess). Thus, there is a clear need to develop an alternative asymmetric synthesis which would provide the desired (+)-trans enantiomer in an efficient and more specific manner.
The object of this invention is to provide an alternative process for the preparation of the (+)-trans enantiomer of the compounds represented by Formula 1, which is an enantioselective process. The process of the present invention allows efficient large-scale synthesis by overcoming the drawbacks of the conventional resolution technique.